In collaboration with internationally recognized experts in H. pylori research, we will focus on the development and validation of the cat and mouse as models to study Helicobacter induced gastroduodenal disease. H. pylori has been firmly established in the etiology of peptic ulcer disease and is now strongly linked to gastric carcinoma and possibly plays a role in MALT gastric lymphoma. Thus, animals models are needed to study the pathogenesis of the disease. Our laboratory has played a pivotal role in developing animal models to study Helicobacter associated gastrointestinal disease. These models are now being widely used by others to study Helicobacter associated pathogenesis and epidemiology. Our laboratory has, either directly or in collaboration with others, isolated, characterized and named 7 new Helicobacter species: H mustelae and H. felis, which infect and induce gastritis in the ferret and rodent respectively; H. muridarium, initially isolated from rodent intestine, which can also colonize rodent stomachs and induce gastritis; H. acinonyx, associated with severe gastric disease in the cheetah; H. hepaticus, which we have established causes persistent hepatitis in mice and in at lest one strain of mice (A/JCr) causes hepatic cancer (this model is being used to study Helicobacter associated carcinogenesis); H. pametensis and H. bilis, isolated from birds and rodents respectively. Recently we identified a closed colony of commercially available cats which have a high prevalence of H. pylori associated gastritis. We have also experimentally colonized SPF cats with the cat H. pylori strain and exensively characterized the cat strains using molecular markers as being indistinguishable from human H. pylori isolates. We have also demonstrated that cats can be persistently infected with a ca+ and vac+ H. pylori strain isolated from a human. In the present proposal, cats infected with vac+ and cag+ strain will be used to study longitudinally, using various in vivo markers of inflammation and proliferation, the pathogenesis of Helicobacter induced disease. Secondly, naive cats will be used to establish whether specific isogenic H. pylori mutants lacking putative virulence factors establish colonization and influence the expression of an inflammatory response. Thirdly, the choice of virulence factors ot be tested in vivo will in part be determined by in vitro assays as well as screening H. pylori isogenic mutants in a mouse model, recently developed in our laboratory.